This invention relates to intermediates useful in the preparation of CETP inhibitors and methods of preparation thereof.
Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S.
Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D. J., et al.: xe2x80x9cHigh-density Lipoprotein Cholesterol and Cardiovascular Diseasexe2x80x9d, Circulation, (1989), 79: 8-15).
High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL-cholesterol are negatively correlated with the risk for developing cardiovascular diseases. Thus, dyslipidernia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.
Among the many factors controlling plasma levels of these disease dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.
No wholly satisfactory HDL-elevating therapies exist. Niacin can significantly increase HDL, but has serious toleration issues resulting in reduced compliance. Fibrates and the HMG-CoA reductase inhibitors raise HDL-C only modestly. As a result, there is a significant unmet medical need for a well-tolerated agent which can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.
PCT application publication number WO 00/02887 discloses the use of catalysts comprising certain novel ligands for transition metals in transition metal-catalyzed carbon-heteroatom and carbonxe2x80x94carbon bond formation.
Commonly assigned U.S. Pat. No. 6,140,343, the disclosure of which is incorporated herein by reference, discloses, inter alia, the CETP inhibitor, cis-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, and processes for the preparation thereof (e.g., procedure disclosed in Example 46).
Commonly assigned U.S. Pat. No. 6,197,786, the disclosure of which is incorporated herein by reference, discloses, inter alia, the CETP inhibitor, cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, and processes for the preparation thereof (e.g., procedure disclosed in Example 7).
One aspect of this invention is the compound of formula III, 
Another aspect of this invention is the compound of formula IV, 
A further aspect of this invention is compounds of formula VI, 
wherein R is selected from methyl, benzyl and substituted benzyl.
An additional aspect of this invention is compounds of formula VII, 
wherein R is selected from methyl, benzyl and substituted benzyl.
In a preferred embodiment of the compound aspects of this invention, R in the compounds of formula VI and the compounds of formula VII is selected from methyl, benzyl and benzyl substituted with one or more substituents each independently selected from (C1-C3)alkyl, (C1-C3)alkyloxy and a halogen.
A further aspect of this invention is methods for preparing the compound of formula 111, above, comprising coupling trifluoromethylbenzene that is para-substituted with a halogen or O-triflate with the compound of formula II, 
to form the compound of formula III.
In a preferred embodiment of the method aspect of this invention relating to preparing the compound of formula III said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a transition metal, preferably palladium.
In another preferred embodiment of the method aspect of this invention relating to preparing the compound of formula III said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a phosphine ligand, preferably a dialkylphosphinobiphenyl ligand, more preferably selected from 2-dicyclohexylphosphino-2xe2x80x2-(N,N-dimethylamino)biphenyl and 2-dicyclohexylphosphino-2xe2x80x2-methylbiphenyl.
In an additional preferred embodiment of the method aspect of this invention relating to preparing the compound of formula III said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a base, preferably cesium carbonate.
Another aspect of this invention is methods for preparing the compound of formula IV, above, comprising hydrolyzing the above compound of formula III, with a hydrolyzing agent selected from an acid and a base, preferably an acid, more preferably sulfuric acid with water, to form the compound of formula IV.
A further aspect of this invention is methods for preparing compounds of formula VI, above, comprising combining the compound of formula IV, above, with a compound of formula V, 
wherein R is selected from methyl, benzyl and substituted benzyl, in the presence of a base, preferably lithium t-butoxide, to form compounds of formula VI.
An additional aspect of this invention is methods for preparing compounds of formula VII, above, comprising reducing the above compounds of formula VI, wherein R is selected from methyl, benzyl and substituted benzyl, with a reducing agent, preferably sodium borohydride in the presence of a Lewis acid, preferably calcium ions or magnesium ions, to form a reduced compound and cyclizing the reduced compound under acidic conditions to form a compound of formula VII.
The term xe2x80x9csubstituted benzylxe2x80x9d with respect to compounds of formula V, VI and VII means benzyl that is substituted on the benzene ring with one or more substituents such that such substitution does not prevent: (a) the reaction of the applicable formula V compound with the compound of formula IV to form the applicable formula VI compounds, (b) the reduction and cyclization of the applicable formula VI to form the applicable formula VIIB compound, (c) the acetylation of the formula VIIB compound to form the formula VIIIB compound or (d) the deprotection step to remove the applicable substituted benzyloxycarbonyl group in forming the formula IB compound from the compound of formula VIIIB. Preferred substituents are (C1-C3)alkyl and (C1-C3)alkoxy and halogens.
Chemical structures herein are represented by planar chemical structure diagrams that are viewed from a perspective above the plane of the structure. A wedge line () appearing in such chemical structures represents a bond that projects up from the plane of the structure.
Reaction Scheme A illustrates the process for preparing the chiral isomer of formula II from (R)-2-amino-1-butanol. Scheme B illustrates the process of preparing the cholesterol ester transfer protein inhibitors of formula IA and formula IB. 
According to Scheme B, the formula III compound is prepared by combining the chiral isomer compound of formula II ((R)-3-amino-pentanenitrile) with trifluoromethylbenzene that is para-substituted with a halogen or O-triflate (xe2x80x94Oxe2x80x94S(O)2CF3) in the presence of a metal catalyst, preferably Pd. For optimal coupling, the coupling reaction occurs in the presence of a ligand, preferably a phosphine ligand, and a base. A preferred phosphine ligand is a dialkylphosphinobiphenyl ligand, preferably selected from 2-dicyclohexylphosphino-2xe2x80x2-(N,N-dimethylamino)biphenyl) and 2-dicyclohexylphosphino-2xe2x80x2-methylbiphenyl. The reaction is preferably performed at a temperature of about 60xc2x0 C. to about 110xc2x0 C. The formula II chiral isomer may be prepared from (R)-2-amino-1-butanol (CAS# 005856-63-3) by methods known to those skilled in the art according to Scheme A and as described in Example 9 of the Experimental Procedures.
The formula IV compound is prepared by hydrolyzing the nitrile of the formula III compound. The hydrolysis may be performed in acidic or basic conditions. The preferred method of hydrolysis is under acidic conditions, preferably using sulfuric acid and water. For hydrolysis with base, preferred bases are hydroxy bases, preferably lithium hydroxide, sodium hydroxide and potassium hydroxide, or alkoxy bases, preferably methoxide and ethoxide. Also, for hydrolysis with base, it is preferably to use a peroxide. The hydrolysis reaction is preferably performed at a temperature of about 20xc2x0 C. to about 40xc2x0 C.
The formula VI compound is prepared by reacting the amide of the formula IV compound with a formula V chloroformate in the presence of a base, preferably lithium t-butoxide. The reaction is preferably performed at a temperature of about 0xc2x0 C. to about 35xc2x0 C. If the formula VI compound having R as methyl is desired, then methyl chloroformate is used as the formula V compound. If the formula VI compound having R as benzyl is desired, then benzyl chloroformate is used.
The formula VII compound is prepared by reacting the imide of the formula VI compound with a reducing agent, preferably sodium borohydride, in the presence of a Lewis acid activator, preferably calcium or magnesium ions to produce a reduced intermediate. The reaction to make the reduced intermediate is preferably performed at a temperature of about xe2x88x9220xc2x0 C. to about 20xc2x0 C. Under acidic conditions, the intermediate diastereoselectively cyclizes to form the tetrahydroquinoline ring of formula VII. The cyclization step is preferably performed at about 20xc2x0 C. to about 50xc2x0 C.
The CETP inhibitor of formula IA is prepared by acylating the compound of formula VII wherein R is methyl at the tetrahydroquinoline nitrogen with ethyl chloroformate in the presence of a base, preferably pyridine, to form the compound of formula VIIIA. The reaction is preferably performed at a temperature of about 0xc2x0 C. to about 25xc2x0 C.
The formula IA CETP inhibitor is prepared by alkylating the formula VIII compound, wherein R is methyl, with a 3,5-bis(trifluoromethyl)benzyl halide, preferably 3,5-bis(trifluoromethyl)benzyl bromide in the presence of a base, preferably an alkoxide or hydroxide, and more preferably potassium t-butoxide. The preferred temperature range of the reaction is about 25xc2x0 C. to about 75xc2x0 C.
The CETP inhibitor of formula IB is prepared by acylating compound VII wherein R is benzyl or substituted benzyl at the tetrahydroquinoline nitrogen with isopropyl chloroformate in the presence of a base, preferably pyridine, to form the compound of formula VIIIB. The preferred temperature of this reaction is about 0xc2x0 C. to about 25xc2x0 C.
The CETP inhibitor of formula IB may then be prepared from the formula VIIIB compound by first treating compound VIIIB with an excess of a hydrogen source (e.g., cyclohexene, hydrogen gas or ammonium formate) in the presence of a suitable catalyst in a polar solvent (e.g. ethanol) to remove the benzyloxycarbonyl group. The 3,5-bis-trifluoromethylbenzyl group of the formula IB compound may then be introduced by treating the amine and an acid, such as acetic acid, with 3,5-bis-trifluoromethyl-benzaldehyde followed by treatment with a hydride source, such as sodium triacetoxyborohydride. Then, the amino group is acetylated by methods known by those skilled in the art to form the formula IB compound. The procedure for preparing the compound of formula IB from the compound of formula VIIIB is further described in Example 46 of commonly assigned U.S. Pat. No. 6,140,343. The disclosure of U.S. Pat. No. 6,140,343 is incorporated herein by reference.
Melting points were determined on a Buchi melting point apparatus. NMR spectra were recorded on a Varian Unity 400 (Varian Co., Palo Alto, Calif.). Chemical shifts are expressed in parts per million downfield from the solvent. The peak shapes are denoted as follows: s=singlet; d=doublet; t=triplet; q=quartet; m=multiplet; bs=broad singlet.